mRNA encoded antibodies in cancer therapy: molecular design, engineered formats, and cellular reprogramming

Abstract Background Antibody-based therapeutics have become a cornerstone of cancer treatment, with over 80 Food and Drug Administration (FDA)- approved secreted proteins and seven chimeric antigen receptor (CAR) cell therapies for various malignancies. Since the introduction of rituximab, the field has evolved from conventional IgG monoclonal antibodies to advanced formats, including antibody-drug conjugates (ADCs), degrader antibody-conjugates (DACs), Fc-engineered antibodies, and bispecific constructs. Immune checkpoint inhibitors targeting PD-1, PD-L1, and CTLA-4 now dominate clinical practice, highlighting the impact of antibody engineering in oncology. Main Body Despite their success, recombinant antibodies and CAR cell therapies require complex manufacturing, high costs, and time-consuming processes, limiting scalability and flexibility. Messenger RNA (mRNA)-based technologies offer an alternative by enabling in vivo production of therapeutic proteins. mRNA-encoded antibodies allow transient synthesis of full-length IgGs, bispecific T-cell engagers, and multiplexed constructs following delivery via lipid nanoparticles or related systems. Although conventional DACs depend on chemical conjugation of antibody scaffolds to non-encoded degrader payloads, recent efforts to develop mRNA-based degrader strategies indicate that the interface between antibody delivery, RNA therapeutics, and targeted protein degradation is beginning to expand. mRNA technology is also used to transiently express chimeric antigen receptors (CARs) in immune cells, enabling non-integrating engineering of T cells, natural killer cells, or macrophages. These approaches support both ex vivo and in vivo generation of CAR-expressing cells, expanding the scope of mRNA therapeutics from protein delivery to cellular reprogramming. The first mRNA-encoded monoclonal antibody dosed in humans (mRNA-1944, NCT03829384) demonstrated dose-dependent therapeutic IgG expression in vivo. In oncology, BNT142 (NCT05262530), an mRNA-encoded bispecific antibody, provided the first clinical efficacy signal for this platform, achieving disease control in over half of treated patients with solid tumors, including partial responses in ovarian cancer. mRNA-electroporated CAR T cell trials (including NCT01355965 targeting mesothelin) established clinical feasibility, and a circular mRNA-based CAR-T (UCMYM802, China) in patients with advanced solid tumors recently became the first of its kind to enter clinical testing. Conclusion Their versatility, rapid design, and tunable expression profiles position mRNA as a programmable platform for next-generation cancer immunotherapies, integrating antibody-, conjugate-, and cell-based modalities.